UC San Diego Bioinformatics Experts
Help Reconstruct
The Genomic Makeup Of Our Ancestors As International
Consortium Completes Rat Genome Sequencing

By Doug Ramsey

Scientists
have generated and begun to analyze the rat genome, paving the
way for comparisons with the two other mammalian genomes sequenced
so far – human, and mouse. The primary results of the
Rat Genome Sequencing Project Consortium (RGSPC) are presented
in the April 1 issue of Nature, and an additional thirty
manuscripts describing further detailed analyses are contained
in the April issue of Genome Research.

The
cover of Genome Research (see end of release) was produced
by University of California, San Diego professors Pavel Pevzner
and Glenn Tesler and their co-author on the journal paper, Guillaume
Bourque of the University of Montreal. It depicts the course
of evolution for the X chromosome in humans, rats and mice from
a common ancestor over 80 million years ago and, for the first
time, reconstructs the genomic architecture of mammalian ancestors.
“It contributes to the solution of the so-called original
synteny problem in biology,” said Pevzner, the Ronald
R. Taylor Professor of Computer Science at UCSD’s Jacobs
School of Engineering. “While scientists routinely find
bones that lead to (often unrealistic) reconstructions of dinosaurs
and other prehistoric animals on movie screens and in toy stores,
this is the first rigorous reconstruction of the genomic makeup
of our mammalian ancestors.”

Pevzner and Tesler are among the more than 200 co-authors of
the Nature article, and expanded on their part of the
research in a Genome Research paper titled “Reconstructing
the Genomic Architecture of Ancestral Mammals: Lessons from
Human, Mouse and Rat Genomes.” “Having the third
genome allows us to reconstruct the putative genomic architecture
of our mammalian ancestor,” said Pevzner. “Our contribution
has been to demonstrate how to look at the human, mouse and
rat genomes – each roughly three billion letters in length
– and then infer the evolutionary earthquakes that shaped
their genomic architectures.”

Pevzner and his colleagues
contend that those earthquakes – major genomic rearrangements
– tend to occur at evolutionary hot spots known as breakpoints,
which are similar to fault zones where earthquakes are more
likely to hit. “We found a few hundred strings of roughly
a million letters long, and we specifically focused on those
large blocks that are shared between the human, mouse and now
rat genomes,” said Tesler, an assistant professor of mathematics
at UCSD. “After sequencing these three genomes, it is
clear that substantial rearrangements in the human genome happen
only once in a million years, while the rate of rearrangements
in the rat and mouse is much faster.”

Comparison of the rat
genome to human and mouse allows a unique view of mammalian
evolution. The rat data shows about 40 percent of the modern
mammalian genome derives from the last common mammalian ancestor.
These ‘core’ one billion bases encode nearly all
the genes and their regulatory signals, accounting for the similarities
among mammals. “We now have information on all three genomes
and we can see how many common architectural blocks we share,”
said Pevzner. “It is almost like a triangle: in the case
of the X chromosome, mouse and rat are about the same distance
apart as rat and human, and human and mouse.”

The study found the
rat genome contains similar numbers of genes to the human and
mouse genomes, but at 2.75 billion nucleotides is smaller than
human (2.9 billion) and slightly larger than mouse (2.6 billion).
Almost all human genes known to be associated with diseases
have counterparts in the rat genome and appear highly conserved
through mammalian evolution. A selected few families of genes
have been expanded in the rat, including smell receptors and
genes for dealing with toxins, and these give clues to the distinctive
physiology of the species.

“The rat genome
allows us to reconstruct the genome’s architecture, especially
for the sex X chromosome, which doesn’t exchange genetic
material with the other chromosome,” explained Pevzner.
“We can come to a very reliable evolutionary scenario
and genomic architecture of the X chromosome. So essentially
we are solving the original phylogeny problem. – how to
reconstruct the genomic architecture of our mammalian ancestor.”

The Rat Genome Sequencing
Project Consortium is led by the Human Genome Sequencing Center
at Baylor College of Medicine (BCM-HGSC) in Houston, in conjunction
with the National Heart, Lung and Blood Institute (NHLBI) and
the National Human Genome Research Institute (NHGRI). “This
is an investment that is destined to yield major payoffs in
the fight against human disease,” said NIH Director Elias
A. Zerhouni, M.D. “For nearly 200 years, the laboratory
rat has played a valuable role in efforts to understand human
biology and to develop new and better drugs. Now, armed with
this sequencing data, a new generation of researchers will be
able to greatly improve the utility of rat models and thereby
improve human health.”

The rat sequence is the third complete mammalian genome to be
sequenced to high quality and described in a major scientific
publication. Three-way comparisons with the human and mouse
genomes will help to resolve details of mammalian evolution.
“The sequencing of the rat genome constitutes another
major milestone in our effort to expand our knowledge of the
human genome,” said NHGRI Director Francis S. Collins,
M.D. “As we build upon the foundation laid by the Human
Genome Project, it’s become clear that comparing the human
genome with those of other organisms is the most powerful tool
available to understand the complex genomic components involved
in human health and disease.”

A network of centers
generated data and resources for the RGSP, including the BCM-HGSC,
Celera Genomics, Genome Therapeutics Corporation, British Columbia
Cancer Agency Genome Sciences Centre, The Institute for Genomic
Research, University of Utah, Medical College of Wisconsin,
The Children’s Hospital of Oakland Research Institute,
and Max-Delbrück-Center for Molecular Medicine (Berlin).
After assembly of the genome at the BCM-HGSC, analysis was performed
by an international team, representing over 20 groups in six
countries and relying largely on gene and protein predictions
produced by the Ensembl project of the EMBL-EBI and Sanger Institute
(UK). Funding for the RGSP was largely provided by the NHLBI
and the NHGRI with additional private funding provided to the
BCM-HGSC by the Kleberg Foundation.